Poor vocational performance, impaired social relations, and inability to live independently are characteristics that have perhaps the greatest impact upon the day-to-day life of patients with schizophrenia (SCZ). Despite the critical impact of these disabilities, there are few data on biological or molecular influences on these functional disabilities. Recent data have suggested that genetic factors may influence clinical domains that may be related to functional disability in SCZ. For example, our group has reported that the dystrobrevin binding protein gene (DTNBP1) is linked with decrements in general cognitive ability and severity of negative symptoms, two manifestations of illness associated with functional disability. This proposal reflects a collaborative effort between psychiatric genetics and functional outcomes researchers aimed at identifying genetic variants that influence functional disability in SCZ. The research strategy combines expertise in the development, utilization and analysis of a novel, validated scale for the assessment of functional disabilities in SCZ with expertise in the collection and analysis of DMA data sets for large scale genetic studies of complex phenotypes. This proposal uses a four-stage genotyping and analytic strategy to "drill down" from an initial broad, whole genome screen towards the dense genotyping of regions implicated in functional disability. Stage 1 involves a whole genome association (WGA) approach in a currently available DNA data set of 500 Caucasian patients with SCZ. WGA, using the Affymetrix 500K chip set, will identify -5,000 single nucleotide polymorphisms (SNPs) that provide the best evidence for association with cognition and negative symptoms, key endophenotypes associated with functional disability. Stage 2 involves the replication of Stage 1 findings in an independent DNA dataset of 500 prospectively collected Caucasian SCZ cases, characterized with the same measures of neurocognition and negative symptoms, to identify the top 25 candidate genes that influence these phenotypes. Stage 3 will then directly test the relationship of Stage 2 confirmed candidate genes with measures of functional disability assessing work function, social function, and residential status and comprehensively genotype the regions surrounding the key SNPs that meet Stage 1 and Stage 2 criteria. Stage 4 involves exploratory analyses of the relationship of Stage 3 confirmed variants to functional disability in 500 SCZ patients from other ethnic groups. At the conclusion of this project, we aim to have identified key molecular variants that influence functional disability in SCZ, as well as related endophenotypes associated with cognitive function and negative symptomatology. Moreover, this project will result in the establishment of the first DNA data sets derived from SCZ patients characterized for functional disability, providing a unique resource for future studies of the molecular genetic influences on this critical characteristic of this disabling illness.